Abstract
Hypoxia-induced upregulation of lincRNA-p21 in tumor tissue was previously shown by our group to be related to poor prognosis in resected non-small cell lung cancer (NSCLC) patients. In the present study, we have evaluated the presence of lincRNA-p21 in extracellular vesicles (EVs) from NSCLC patients and assessed its potential as a prognostic biomarker. High EV lincRNA-p21 levels in blood from the tumor-draining vein were associated with shorter time to relapse and shorter overall survival. Moreover, the multivariate analysis identified high lincRNA-p21 levels as an independent prognostic marker. In addition, lincRNA-p21 was overexpressed in H23 and HCC44 NSCLC cell lines and their derived EVs under hypoxic conditions. Functional assays using human umbilical vein endothelial cells (HUVECs) showed that tumor-derived EVs enriched in lincRNA-p21 affected endothelial cells by promoting tube formation and enhancing tumor cell adhesion to endothelial cells. Additionally, the analysis of selected EV microRNAs related to angiogenesis and metastasis showed that the microRNAs correlated with EV lincRNA-p21 levels in both patients and cell lines. Finally, EV co-culture with HUVEC cells increased the expression of microRNAs and genes related to endothelial cell activation. In conclusion, EV lincRNA-p21 acts as a novel prognosis marker in resected NSCLC patients, promoting angiogenesis and metastasis.
Highlights
Lung cancer is the most common cancer, accounting for 2.1 million new cases annually, and is the leading cause of death from cancer, with 1.8 million deaths per year [1]
We showed that the oncogenic role of lincRNA-p21 in non-small cell lung cancer (NSCLC) was associated with hypoxia and regulation of angiogenesis [29]
This study was conducted in a cohort of 56 resected NSCLC patients with available blood from the tumor-draining pulmonary vein, obtained during surgery
Summary
Lung cancer is the most common cancer, accounting for 2.1 million new cases annually, and is the leading cause of death from cancer, with 1.8 million deaths per year [1]. In early-stage non-small-cell lung cancer (NSCLC) [2], potentially curative surgery is the gold standard of treatment, combined. Up to 40% of resected patients with stage I, II, or IIIA will relapse in the first five years after surgery [4], indicating the urgent need to develop new biomarkers to identify patients at high risk of relapse to improve their survival rates after surgery. Our group has previously shown that primary tumor-related EVs can be obtained from the tumor-draining pulmonary vein in resected patients and that the study of their physical characteristics, including quantity and size, from this source can be a promising tool to identify high-risk patients [10]. In our previous manuscript, we did not explored the potential role of EVs cargo studied in tumor-draining pulmonary vein samples
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